Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation.

Retinoic acid (RA) can induce growth arrest and neuronal differentiation of neuroblastoma cells and has been used in clinic for treatment of neuroblastoma. It has been reported that RA induces the expression of several HOXD genes in human neuroblastoma cell lines, but their roles in RA action are la...

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Main Authors: Yunhong Zha, Emily Ding, Liqun Yang, Ling Mao, Xiangwei Wang, Brian A McCarthy, Shuang Huang, Han-Fei Ding
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2012-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3413684?pdf=render
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spelling doaj-060f9c4889c14861a3e80aca831e84562020-11-25T01:48:34ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0178e4072810.1371/journal.pone.0040728Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation.Yunhong ZhaEmily DingLiqun YangLing MaoXiangwei WangBrian A McCarthyShuang HuangHan-Fei DingRetinoic acid (RA) can induce growth arrest and neuronal differentiation of neuroblastoma cells and has been used in clinic for treatment of neuroblastoma. It has been reported that RA induces the expression of several HOXD genes in human neuroblastoma cell lines, but their roles in RA action are largely unknown. The HOXD cluster contains nine genes (HOXD1, HOXD3, HOXD4, and HOXD8-13) that are positioned sequentially from 3' to 5', with HOXD1 at the 3' end and HOXD13 the 5' end. Here we show that all HOXD genes are induced by RA in the human neuroblastoma BE(2)-C cells, with the genes located at the 3' end being activated generally earlier than those positioned more 5' within the cluster. Individual induction of HOXD8, HOXD9, HOXD10 or HOXD12 is sufficient to induce both growth arrest and neuronal differentiation, which is associated with downregulation of cell cycle-promoting genes and upregulation of neuronal differentiation genes. However, induction of other HOXD genes either has no effect (HOXD1) or has partial effects (HOXD3, HOXD4, HOXD11 and HOXD13) on BE(2)-C cell proliferation or differentiation. We further show that knockdown of HOXD8 expression, but not that of HOXD9 expression, significantly inhibits the differentiation-inducing activity of RA. HOXD8 directly activates the transcription of HOXC9, a key effector of RA action in neuroblastoma cells. These findings highlight the distinct functions of HOXD genes in RA induction of neuroblastoma cell differentiation.http://europepmc.org/articles/PMC3413684?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Yunhong Zha
Emily Ding
Liqun Yang
Ling Mao
Xiangwei Wang
Brian A McCarthy
Shuang Huang
Han-Fei Ding
spellingShingle Yunhong Zha
Emily Ding
Liqun Yang
Ling Mao
Xiangwei Wang
Brian A McCarthy
Shuang Huang
Han-Fei Ding
Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation.
PLoS ONE
author_facet Yunhong Zha
Emily Ding
Liqun Yang
Ling Mao
Xiangwei Wang
Brian A McCarthy
Shuang Huang
Han-Fei Ding
author_sort Yunhong Zha
title Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation.
title_short Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation.
title_full Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation.
title_fullStr Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation.
title_full_unstemmed Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation.
title_sort functional dissection of hoxd cluster genes in regulation of neuroblastoma cell proliferation and differentiation.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2012-01-01
description Retinoic acid (RA) can induce growth arrest and neuronal differentiation of neuroblastoma cells and has been used in clinic for treatment of neuroblastoma. It has been reported that RA induces the expression of several HOXD genes in human neuroblastoma cell lines, but their roles in RA action are largely unknown. The HOXD cluster contains nine genes (HOXD1, HOXD3, HOXD4, and HOXD8-13) that are positioned sequentially from 3' to 5', with HOXD1 at the 3' end and HOXD13 the 5' end. Here we show that all HOXD genes are induced by RA in the human neuroblastoma BE(2)-C cells, with the genes located at the 3' end being activated generally earlier than those positioned more 5' within the cluster. Individual induction of HOXD8, HOXD9, HOXD10 or HOXD12 is sufficient to induce both growth arrest and neuronal differentiation, which is associated with downregulation of cell cycle-promoting genes and upregulation of neuronal differentiation genes. However, induction of other HOXD genes either has no effect (HOXD1) or has partial effects (HOXD3, HOXD4, HOXD11 and HOXD13) on BE(2)-C cell proliferation or differentiation. We further show that knockdown of HOXD8 expression, but not that of HOXD9 expression, significantly inhibits the differentiation-inducing activity of RA. HOXD8 directly activates the transcription of HOXC9, a key effector of RA action in neuroblastoma cells. These findings highlight the distinct functions of HOXD genes in RA induction of neuroblastoma cell differentiation.
url http://europepmc.org/articles/PMC3413684?pdf=render
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